Angewandte. Essays International Edition: DOI: 10.1002/anie.201503375 Supramolecular Systems German Edition: DOI: 10.1002/ange.201503375 Rise of the Molecular Machines Euan R. Kay* and David A. Leigh* molecular devices · molecular machines · molecular motors · molecular nanotechnology Introduction inspirational in general terms, it is doubtful whether either of these manifestos had much practical influence on the devel- “When we get to the very, very small world … we have a lot of opment of artificial molecular machines.[5] Feynmans talk new things that would happen that represent completely new came at a time before chemists had the synthetic methods and opportunities for design … At the atomic level we have new kinds analytical tools available to be able to consider how to make of forces and new kinds of possibilities, new kinds of effects. The molecular machines; Drexlers somewhat nonchemical view problem of manufacture and reproduction of materials will be of atomic construction is not shared by the majority of quite different … inspired by biological phenomena in which experimentalists working in this area. In fact, “mechanical” chemical forces are used in a repetitious fashion to produce all movement within molecules has been part of chemistry since kinds of weird effects (one of which is the author) …” conformational analysis became established in the 1950s.[6] As Richard P. Feynman (1959)[2] well as being central to advancing the structural analysis of complex molecules, this was instrumental in chemists begin- It has long been appreciated that molecular motors and ning to consider dynamics as an intrinsic aspect of molecular machines are central to almost every biological process. The structure and hence a property they could aspire to control. harvesting of energy from the sun, the storing of energy, Artificial systems were designed to exhibit particular con- transporting cargoes around the cell, the movement of cells, formational behavior, such as the “cog-wheeling”-correlated generation of force (at both the molecular and macroscopic motions of aromatic “blades” in triptycenes and related levels), replication, transcription, translation, synthesis, driv- structures constructed by the groups of O¯ ki, Mislow, and ing chemical systems away from equilibrium, etc.—virtually Iwamura in the 1970s and 1980s (e.g. 1, Figure 1a).[7] Before every biological task involves molecular machines.[1] Given long, stimuli-induced changes in conformation had been used the success of mankinds machines in the macroscopic world, to control molecular recognition properties; two of the from the Stone-Age wheel to the modern-day smart phone, it seminal examples being Rebeks use of allostery[8] (binding was inevitable that we should one day seek to achieve the at one site influencing binding affinity at a second site; 2, ultimate in machine miniaturization. However, it has taken Figure 1b) and Shinkais azobenzene photoswitch[9] for some time to gain sufficient mastery over the necessary modulating the cation-binding properties of crown ethers (3, synthetic and supramolecular chemistry (and related physics) Figure 1c). However, the field of synthetic molecular ma- for this field to begin to flourish. chines really began to take off with developments that Richard Feynmans classic 1959 lecture Theres plenty of occurred in the early 1990s. room at the bottom[2] outlined some of the promise that man- made molecular machines might hold, a scientific “taster” that Eric Drexler embraced for his controversial[3] vision of Architectures for Well-Defined Large-Amplitude “nanobots” and “molecular assemblers”.[4] However, whilst Molecular-Level Motions In many ways the field of artificial molecular machinery [*] Dr. E. R. Kay EaStCHEM School of Chemistry, University of St Andrews began with J. Fraser Stoddarts invention of a “molecular [10] North Haugh, St Andrews KY16 9ST (UK) shuttle” (4) in 1991 (Figure 2). In this rotaxane (a molecule E-mail: [email protected] with a ring mechanically locked onto an axle by bulky Homepage: http://kaylab.wp.st-andrews.ac.uk stoppers), the ring (shown in blue) moves between two Prof. D. A. Leigh preferred binding sites (the two hydroquinone units, shown in School of Chemistry, University of Manchester red) by random thermal motion (Brownian motion). The use Oxford Road, Manchester M13 9PL (UK) of template effects to assemble mechanically linked mole- E-mail: [email protected] cules (catenanes and, later, rotaxanes) had been introduced Homepage: http://www.catenane.net by Jean-Pierre Sauvage in the early 1980s;[11] Stoddarts great 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. insight was to recognize that the threaded (mechanically KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and interlocked) architecture of a rotaxane could allow for the reproduction in any medium, provided the original work is properly large-amplitude motion of molecular-level components in cited. a well-defined and potentially controllable manner. The 2 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2015, 54,2–11 Ü Ü These are not the final page numbers! Angewandte Chemie authors of the 1991 JACS paper noted: “Insofar as it becomes possible to control the movement of one molecular compo- nent with respect to the other in a [2]rotaxane, the technology for building molecular machines will emerge.”[10] This statement turned out to be highly prescient and the paper hugely influential. Although mechanically interlocked structures are not necessary to construct molecular machines (see below), they provided the first practical synthetic molecular architecture through which well-defined large- amplitude molecular-level motions could be selectively ad- dressed, studied, and utilized.[1b–g] This gave an exciting and compelling reason to make rotaxanes and catenanes, and the area burgeoned from these molecules being academic curi- osities in the 1960s (when catenanes and rotaxanes were first made by long and/or inefficient synthetic routes[12]) through to 1989 (when Stoddart and co-workers made their first cate- nane,[13] six years after Sauvage and co-workers revolution- ized the strategy for their synthesis through the use of template methods[11]) to the mainstream area it is now,[14] with hundreds of groups active in this field from the mid-1990s onwards. Switching the Relative Positions of Molecular Components—From Molecules to Machines By desymmetrizing a rotaxane thread to have two differ- ent potential binding sites, or “stations”, whose relative affinity for the ring could be switched, Stoddart, Kaifer, and co-workers arguably invented the first artificial molecular Brownian motion machine (5, Figure 3).[15] The cationic ring Figure 1. Correlated intramolecular motions within “proto-molecular (shown in dark blue) prefers to reside over the benzidine machines”: a) Intramolecular mechanical cog-wheeling (this example, Iwamura et al.; 1983);[7] b) a negative heterotopic allosteric receptor (Rebek et al.; 1979);[8] c) photoswitchable binding of a crown ether (Shinkai et al.; 1980).[9] Euan Kay received his MChem from the University of Edinburgh in 2002 and his PhD in 2006 under the supervision of David Leigh. He was the recipient of a 2007 IUPAC Prize for Young Chemists. Following group (shown in light blue) rather than the biphenol site postdoctoral work in Edinburgh, he joined (shown in orange). However, protonation (or electrochemical Prof. Moungi Bawendi at MIT (2008– oxidation) of the benzidine station (now in purple) renders 2010). Since 2011, he has been a Royal the biphenol group the preferred binding site for the cationic Society of Edinburgh/Scottish Government ring, thereby causing a net displacement of the ring along the Personal Research Fellow at the University track. This system marks the first example of a large- of St Andrews. His research interests focus on translating dynamic and stimuli-respon- amplitude, well-defined, controlled switching of the position sive (supra)molecular systems into the of a component along a molecular track. nanoworld. The groups of Stoddart and others (notably those of David Leigh was born in Birmingham and Sauvage, Balzani, Fujita, Hunter, Vçgtle, Sanders, Beer, and obtained his BSc and PhD from the Uni- Leigh) contributed to the development of many other versity of Sheffield. After postdoctoral re- rotaxane- and catenane-forming motifs and strategies over search in Ottawa (1987–1989), he was the period 1992–2007,[1b,f,g] and invented many different ways appointed to a Lectureship at the University of switching the positions of the components in rotaxane and of Manchester Institute of Science and Technology. After spells at the Universities of catenane architectures with various stimuli (light, electro- Warwick and Edinburgh he returned to chemistry, pH value, polarity of the environment, cation Manchester in 2012, where he currently binding, anion binding, allosteric effects, temperature, rever- holds the Sir Samuel Hall Chair of sible covalent-bond formation, etc).[1b,f,g] The next key ad- Chemistry. He was elected a Fellow of the vance needed was—and in some respects still is—to find ways Royal Society in 2009. His research interests to use the change of the position of the components of include chemical topology and synthetic a molecular machine to perform useful tasks (see below). molecular-level motors and machines. Angew. Chem. Int. Ed.